We have studied the regulatory actions of aldose reductase inhibition and myo-inositol (MI) supplementation during the onset and reversal of sugar cataract over the past 10 years. In the reversal studies, we found that a direct correlation existed between lens MI content, cell integrity and lens transparency using 2 animal models of diabetes (galactose maintained and STZ-induced diabetic rat). Since MI is a precursor for synthesis of phosphatidylinositol (PI) and PI may act as an endogenous regular of Na, K- ATPase, MI is essential in cell proliferation and homeostasis. The hypothesis has been proposed that the decreased intracellular MI causes or at least contributes to diabetic complications such as neuropathies, nephropathies and cataracts. Our primary objective of the proposed research is to study in detail the potential contributions of disturbances of the metabolism due to hyperglycemia on development of diabetic cataract. The specific goals are: 1) to continue the investigation of changes in PI and other phospholipids in galactose-maintained and STZ-induced diabetic rats; 2) to determine the membrane mechanism regulating intracellular MI concentration in epithelial cells by measuring influx and efflux of MI; 3) to study the effects of D- glucose and other hexoses on MI transport in whole lens and cultured epithelial cells; 4) to assess the effects of MI deficiency on cell homeostasis represented by PI levels, Na-K-ATPase activity and changes in intracellular electrolyte composition; and 5) study the effects of elevated D-glucose concentrations on the parameters listed under 4. Lastly we will investigate whether increased extracellular MI concentrations can prevent or reverse the changes observed under 5 and determine whether elevated MI can have a therapeutic benefit. The experiments are designed to lead to a comprehensive understanding of the effects of hyperglycemia on the homeostasis of lens epithelial cells and the possibility of modifying the extent and rate of the cataract reparative process by manipulation of MI. Our long term objective is to enhance lens integrity in patients who exhibit various stages of diabetic cataract.